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Alpha-1 antitrypsin deficiency

Reviewed January 2013

What is alpha-1 antitrypsin deficiency?

Alpha-1 antitrypsin deficiency is an inherited disorder that may cause lung disease and liver disease. The signs and symptoms of the condition and the age at which they appear vary among individuals.

People with alpha-1 antitrypsin deficiency usually develop the first signs and symptoms of lung disease between ages 20 and 50. The earliest symptoms are shortness of breath following mild activity, reduced ability to exercise, and wheezing. Other signs and symptoms can include unintentional weight loss, recurring respiratory infections, fatigue, and rapid heartbeat upon standing. Affected individuals often develop emphysema, which is a lung disease caused by damage to the small air sacs in the lungs (alveoli). Characteristic features of emphysema include difficulty breathing, a hacking cough, and a barrel-shaped chest. Smoking or exposure to tobacco smoke accelerates the appearance of emphysema symptoms and damage to the lungs.

About 10 percent of infants with alpha-1 antitrypsin deficiency develop liver disease, which often causes yellowing of the skin and whites of the eyes (jaundice). Approximately 15 percent of adults with alpha-1 antitrypsin deficiency develop liver damage (cirrhosis) due to the formation of scar tissue in the liver. Signs of cirrhosis include a swollen abdomen, swollen feet or legs, and jaundice. Individuals with alpha-1 antitrypsin deficiency are also at risk of developing a type of liver cancer called hepatocellular carcinoma.

In rare cases, people with alpha-1 antitrypsin deficiency develop a skin condition called panniculitis, which is characterized by hardened skin with painful lumps or patches. Panniculitis varies in severity and can occur at any age.

How common is alpha-1 antitrypsin deficiency?

Alpha-1 antitrypsin deficiency occurs worldwide, but its prevalence varies by population. This disorder affects about 1 in 1,500 to 3,500 individuals with European ancestry. It is uncommon in people of Asian descent. Many individuals with alpha-1 antitrypsin deficiency are likely undiagnosed, particularly people with a lung condition called chronic obstructive pulmonary disease (COPD). COPD can be caused by alpha-1 antitrypsin deficiency; however, the alpha-1 antitrypsin deficiency is often never diagnosed. Some people with alpha-1 antitrypsin deficiency are misdiagnosed with asthma.

What genes are related to alpha-1 antitrypsin deficiency?

Mutations in the SERPINA1 gene cause alpha-1 antitrypsin deficiency. This gene provides instructions for making a protein called alpha-1 antitrypsin, which protects the body from a powerful enzyme called neutrophil elastase. Neutrophil elastase is released from white blood cells to fight infection, but it can attack normal tissues (especially the lungs) if not tightly controlled by alpha-1 antitrypsin.

Mutations in the SERPINA1 gene can lead to a shortage (deficiency) of alpha-1 antitrypsin or an abnormal form of the protein that cannot control neutrophil elastase. Without enough functional alpha-1 antitrypsin, neutrophil elastase destroys alveoli and causes lung disease. Abnormal alpha-1 antitrypsin can also accumulate in the liver and damage this organ.

Environmental factors, such as exposure to tobacco smoke, chemicals, and dust, likely impact the severity of alpha-1 antitrypsin deficiency.

Related Gene(s)

Changes in this gene are associated with alpha-1 antitrypsin deficiency.

  • SERPINA1

How do people inherit alpha-1 antitrypsin deficiency?

This condition is inherited in an autosomal codominant pattern. Codominance means that two different versions of the gene may be active (expressed), and both versions contribute to the genetic trait.

The most common version (allele) of the SERPINA1 gene, called M, produces normal levels of alpha-1 antitrypsin. Most people in the general population have two copies of the M allele (MM) in each cell. Other versions of the SERPINA1 gene lead to reduced levels of alpha-1 antitrypsin. For example, the S allele produces moderately low levels of this protein, and the Z allele produces very little alpha-1 antitrypsin. Individuals with two copies of the Z allele (ZZ) in each cell are likely to have alpha-1 antitrypsin deficiency. Those with the SZ combination have an increased risk of developing lung diseases (such as emphysema), particularly if they smoke.

Worldwide, it is estimated that 161 million people have one copy of the S or Z allele and one copy of the M allele in each cell (MS or MZ). Individuals with an MS (or SS) combination usually produce enough alpha-1 antitrypsin to protect the lungs. People with MZ alleles, however, have a slightly increased risk of impaired lung or liver function.

Where can I find information about diagnosis or management of alpha-1 antitrypsin deficiency?

These resources address the diagnosis or management of alpha-1 antitrypsin deficiency and may include treatment providers.

  • Alpha-1 Foundation: Get Tested (http://alpha-1foundation.org/get-tested/)
  • Cleveland Clinic Respiratory Institute (http://my.clevelandclinic.org/lungs-breathing-allergy/departments-centers/alpha-1-antitrypsin-deficiency-center.aspx)
  • GeneFacts: Alpha-1 Antitrypsin Deficiency: Diagnosis (http://genefacts.org/index.php?option=com_content&view=article&id=511&Itemid=740)
  • GeneFacts: Alpha-1 Antitrypsin Deficiency: Management (http://genefacts.org/index.php?option=com_content&view=article&id=512&Itemid=741)
  • Gene Review: Alpha1-Antitrypsin Deficiency (http://www.ncbi.nlm.nih.gov/books/NBK1519/)
  • Genetic Testing Registry: Alpha-1-antitrypsin deficiency (http://www.ncbi.nlm.nih.gov/gtr/conditions/C0221757)
  • MedlinePlus Encyclopedia: Alpha-1 antitrypsin deficiency (http://www.nlm.nih.gov/medlineplus/ency/article/000120.htm)
  • MedlinePlus Encyclopedia: Pulmonary function tests (http://www.nlm.nih.gov/medlineplus/ency/article/003853.htm)
  • MedlinePlus Encyclopedia: Wheezing (http://www.nlm.nih.gov/medlineplus/ency/article/003070.htm)

You might also find information on the diagnosis or management of alpha-1 antitrypsin deficiency in Educational resources (http://ghr.nlm.nih.gov/condition/alpha-1-antitrypsin-deficiency/show/Educational+resources) and Patient support (http://ghr.nlm.nih.gov/condition/alpha-1-antitrypsin-deficiency/show/Patient+support).

General information about the diagnosis (http://ghr.nlm.nih.gov/handbook/consult/diagnosis) and management (http://ghr.nlm.nih.gov/handbook/consult/treatment) of genetic conditions is available in the Handbook. Read more about genetic testing (http://ghr.nlm.nih.gov/handbook/testing), particularly the difference between clinical tests and research tests (http://ghr.nlm.nih.gov/handbook/testing/researchtesting).

To locate a healthcare provider, see How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

Where can I find additional information about alpha-1 antitrypsin deficiency?

You may find the following resources about alpha-1 antitrypsin deficiency helpful. These materials are written for the general public.

You may also be interested in these resources, which are designed for healthcare professionals and researchers.

What other names do people use for alpha-1 antitrypsin deficiency?

  • AAT
  • AATD
  • alpha-1 protease inhibitor deficiency
  • alpha-1 related emphysema
  • genetic emphysema
  • hereditary pulmonary emphysema
  • inherited emphysema

For more information about naming genetic conditions, see the Genetics Home Reference Condition Naming Guidelines (http://ghr.nlm.nih.gov/ConditionNameGuide) and How are genetic conditions and genes named? (http://ghr.nlm.nih.gov/handbook/mutationsanddisorders/naming) in the Handbook.

What if I still have specific questions about alpha-1 antitrypsin deficiency?

Ask the Genetic and Rare Diseases Information Center (http://rarediseases.info.nih.gov/GARD/).

What glossary definitions help with understanding alpha-1 antitrypsin deficiency?

allele ; alveoli ; autosomal ; cancer ; carcinoma ; cell ; chronic ; chronic obstructive pulmonary disease ; cirrhosis ; codominance ; COPD ; deficiency ; emphysema ; enzyme ; expressed ; gene ; hepatocellular carcinoma ; hereditary ; infection ; inherited ; jaundice ; liver cancer ; obstructive ; panniculitis ; population ; prevalence ; protease ; protein ; pulmonary ; pulmonary emphysema ; respiratory ; tissue ; trait ; wheezing ; white blood cells

You may find definitions for these and many other terms in the Genetics Home Reference Glossary (http://ghr.nlm.nih.gov/glossary).

References

  • Carrell RW, Lomas DA. Alpha1-antitrypsin deficiency--a model for conformational diseases. N Engl J Med. 2002 Jan 3;346(1):45-53. Review. (http://www.ncbi.nlm.nih.gov/pubmed/11778003?dopt=Abstract)
  • DeMeo DL, Silverman EK. Alpha1-antitrypsin deficiency. 2: genetic aspects of alpha(1)-antitrypsin deficiency: phenotypes and genetic modifiers of emphysema risk. Thorax. 2004 Mar;59(3):259-64. Review. (http://www.ncbi.nlm.nih.gov/pubmed/14985567?dopt=Abstract)
  • de Serres FJ, Blanco I, Fernández-Bustillo E. Estimated numbers and prevalence of PI*S and PI*Z deficiency alleles of alpha1-antitrypsin deficiency in Asia. Eur Respir J. 2006 Dec;28(6):1091-9. Epub 2006 Sep 27. (http://www.ncbi.nlm.nih.gov/pubmed/17005586?dopt=Abstract)
  • de Serres FJ, Blanco I, Fernández-Bustillo E. Estimating the risk for alpha-1 antitrypsin deficiency among COPD patients: evidence supporting targeted screening. COPD. 2006 Aug;3(3):133-9. Erratum in: COPD. 2006 Dec;3(4):245. (http://www.ncbi.nlm.nih.gov/pubmed/17240615?dopt=Abstract)
  • de Serres FJ, Blanco I, Fernández-Bustillo E. Health implications of alpha1-antitrypsin deficiency in Sub-Sahara African countries and their emigrants in Europe and the New World. Genet Med. 2005 Mar;7(3):175-84. Review. (http://www.ncbi.nlm.nih.gov/pubmed/15775753?dopt=Abstract)
  • de Serres FJ, Blanco I, Fernández-Bustillo E. PI S and PI Z alpha-1 antitrypsin deficiency worldwide. A review of existing genetic epidemiological data. Monaldi Arch Chest Dis. 2007 Dec;67(4):184-208. Review. (http://www.ncbi.nlm.nih.gov/pubmed/18309698?dopt=Abstract)
  • de Serres FJ. Alpha-1 antitrypsin deficiency is not a rare disease but a disease that is rarely diagnosed. Environ Health Perspect. 2003 Dec;111(16):1851-4. Review. (http://www.ncbi.nlm.nih.gov/pubmed/14654440?dopt=Abstract)
  • Fairbanks KD, Tavill AS. Liver disease in alpha 1-antitrypsin deficiency: a review. Am J Gastroenterol. 2008 Aug;103(8):2136-41; quiz 2142. doi: 10.1111/j.1572-0241.2008.01955.x. Review. (http://www.ncbi.nlm.nih.gov/pubmed/18796107?dopt=Abstract)
  • Fregonese L, Stolk J. Hereditary alpha-1-antitrypsin deficiency and its clinical consequences. Orphanet J Rare Dis. 2008 Jun 19;3:16. doi: 10.1186/1750-1172-3-16. Review. (http://www.ncbi.nlm.nih.gov/pubmed/18565211?dopt=Abstract)
  • Gene Review: Alpha1-Antitrypsin Deficiency (http://www.ncbi.nlm.nih.gov/books/NBK1519/)
  • Lomas DA, Parfrey H. Alpha1-antitrypsin deficiency. 4: Molecular pathophysiology. Thorax. 2004 Jun;59(6):529-35. Review. (http://www.ncbi.nlm.nih.gov/pubmed/15170041?dopt=Abstract)
  • Luisetti M, Seersholm N. Alpha1-antitrypsin deficiency. 1: epidemiology of alpha1-antitrypsin deficiency. Thorax. 2004 Feb;59(2):164-9. Review. (http://www.ncbi.nlm.nih.gov/pubmed/14760160?dopt=Abstract)
  • Needham M, Stockley RA. Alpha 1-antitrypsin deficiency. 3: Clinical manifestations and natural history. Thorax. 2004 May;59(5):441-5. Review. (http://www.ncbi.nlm.nih.gov/pubmed/15115878?dopt=Abstract)
  • Perlmutter DH, Brodsky JL, Balistreri WF, Trapnell BC. Molecular pathogenesis of alpha-1-antitrypsin deficiency-associated liver disease: a meeting review. Hepatology. 2007 May;45(5):1313-23. Review. (http://www.ncbi.nlm.nih.gov/pubmed/17464974?dopt=Abstract)
  • Ranes J, Stoller JK. A review of alpha-1 antitrypsin deficiency. Semin Respir Crit Care Med. 2005 Apr;26(2):154-66. Review. (http://www.ncbi.nlm.nih.gov/pubmed/16088434?dopt=Abstract)
  • Stoller JK, Aboussouan LS. Myths and misconceptions about {alpha}1-antitrypsin deficiency. Arch Intern Med. 2009 Mar 23;169(6):546-50. doi: 10.1001/archinternmed.2009.25. (http://www.ncbi.nlm.nih.gov/pubmed/19307516?dopt=Abstract)
  • Teckman JH, Lindblad D. Alpha-1-antitrypsin deficiency: diagnosis, pathophysiology, and management. Curr Gastroenterol Rep. 2006 Feb;8(1):14-20. Review. (http://www.ncbi.nlm.nih.gov/pubmed/16510030?dopt=Abstract)
  • Teckman JH. Alpha1-antitrypsin deficiency in childhood. Semin Liver Dis. 2007 Aug;27(3):274-81. Review. (http://www.ncbi.nlm.nih.gov/pubmed/17682974?dopt=Abstract)

 

The resources on this site should not be used as a substitute for professional medical care or advice. Users seeking information about a personal genetic disease, syndrome, or condition should consult with a qualified healthcare professional. See How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

 
Reviewed: January 2013
Published: August 25, 2014